Feverfew (Tanacetum parthenium) has a long history of use for analgesic and anti-inflammatory effects. Some, but not all, controlled trials have shown beneficial effects of feverfew powder or extracts in migraine. Studies which have primarily been done in cell cultures have shown that parthenolide and other sesquiterpene lactones in feverfew extracts may have anti-inflammatory effects mediated by inhibiting the signaling enzyme I-kappa- kinase (I-kappaK) and/or the transcription factor NF-kappaB. However, there have been few studies of the importance of these effects in animal models of human disease. Furthermore, it is not clear how the anti-inflammatory effects of feverfew relate to its anti-migraine activities. Cystic Fibrosis (CF) is the most common genetic cause of early death amongst Caucasians. Multiple lines of evidence from human, mouse and cell culture studies all suggest that CF lung disease is characterized by inflammatory responses which are excessive because of exaggerated production of NF-kappaB dependent cytokines and adhesion molecules. Additional evidence suggests that this, in turn, may be due to excessive activation of I-kappaK and depletion of its substrate, I-kappaB, following inflammatory stimuli. Decreases in I-kappaB lead to excessive and prolonged NF-kB activation and excessive NF-kB dependent pro-inflammatory gene transcription. Our hypothesis is that feverfew extracts and parthenolide will attenuate the excessive inflammatory responses in mouse models of CF lung disease by inhibiting I-kappaK activity and/or DNA binding of NF-kappaB. To test this, we will determine the effects of parthenolide and feverfew extracts on I-kappaK activity, I-kappaB protein, NF-kappaB and lung and systemic inflammatory responses in CF mice after intratracheal challenge with LPS, acute lung infection with P. aeruginosa (P.a.), and chronic lung infection with P.a. We will also determine if p38 MAP kinase, JNK and/or AP-1 pathways are affected by these potential therapeutic agents. Results of these studies should not only help to define the anti-inflammatory mechanisms of feverfew in vivo, they should also pave the way for clinical trials of feverfew and/or parthenolide in CF and provide a basis for future studies aimed at determining how their anti-inflammatory effects relate to their use in migraine.